| First Author | Douchi D | Year | 2021 |
| Journal | Gastroenterology | Volume | 161 |
| Issue | 6 | Pages | 1907-1923.e26 |
| PubMed ID | 34391772 | Mgi Jnum | J:314694 |
| Mgi Id | MGI:6825620 | Doi | 10.1053/j.gastro.2021.08.013 |
| Citation | Douchi D, et al. (2021) Induction of Gastric Cancer by Successive Oncogenic Activation in the Corpus. Gastroenterology 161(6):1907-1923.e26 |
| abstractText | BACKGROUND & AIMS: Metaplasia and dysplasia in the corpus are reportedly derived from de-differentiation of chief cells. However, the cellular origin of metaplasia and cancer remained uncertain. Therefore, we investigated whether pepsinogen C (PGC) transcript-expressing cells represent the cellular origin of metaplasia and cancer using a novel Pgc-specific CreERT2 recombinase mouse model. METHODS: We generated a Pgc-mCherry-IRES-CreERT2 (Pgc-CreERT2) knock-in mouse model. Pgc-CreERT2/(+) and Rosa-EYFP mice were crossed to generate Pgc-CreERT2/Rosa-EYFP (Pgc-CreERT2/YFP) mice. Gastric tissues were collected, followed by lineage-tracing experiments and histologic and immunofluorescence staining. We further established Pgc-CreERT2;Kras(G12D/+) mice and investigated whether PGC transcript-expressing cells are responsible for the precancerous state in gastric glands. To investigate cancer development from PGC transcript-expressing cells with activated Kras, inactivated Apc, and Trp53 signaling pathways, we crossed Pgc-CreERT2/(+) mice with conditional Kras(G12D), Apc(flox), Trp53(flox) mice. RESULTS: Expectedly, mCherry mainly labeled chief cells in the Pgc-CreERT2 mice. However, mCherry was also detected throughout the neck cell and isthmal stem/progenitor regions, albeit at lower levels. In the Pgc-CreERT2;Kras(G12D/+) mice, PGC transcript-expressing cells with Kras(G12D/+) mutation presented pseudopyloric metaplasia. The early induction of proliferation at the isthmus may reflect the ability of isthmal progenitors to react rapidly to Pgc-driven Kras(G12D/+) oncogenic mutation. Furthermore, Pgc-CreERT2;Kras(G12D/+);Apc(flox/flox) mice presented intramucosal dysplasia/carcinoma and Pgc-CreERT2;Kras(G12D/+);Apc(flox/flox);Trp53(flox/flox) mice presented invasive and metastatic gastric carcinoma. CONCLUSIONS: The Pgc-CreERT2 knock-in mouse is an invaluable tool to study the effects of successive oncogenic activation in the mouse corpus. Time-course observations can be made regarding the responses of isthmal and chief cells to oncogenic insults. We can observe stomach-specific tumorigenesis from the beginning to metastatic development. |
